# A Tolerance Approach to Xenotransplantation

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $3,294,103

## Abstract

This proposal represents the renewal of a highly integrated PPG aimed at induction of tolerance to porcine
organs transplanted into primates. We propose to combine two unique tolerance induction platforms, one based
on mixed hematopoietic chimerism and the other on vascularized thymus transplantation. CRISPR/Cas9
technology is used to modify our inbred miniature swine genetically in order to increase the level and duration of
mixed chimerism as well as to enhance organ survival. In Project 1, “Achieving Xenograft Tolerance through
Thymic Programming in Primates”, we will advance the vascularized thymus (VT) approach to kidney xenograft
tolerance toward a clinical trial (Aim 1). In Aim 2, we will attempt to optimize tolerance by combining deletional
and Treg-mediated mechanisms while also tolerizing B cells to the inbred SLAhh GalT KO pig kidney donor. This
tolerance will be achieved by combining the VT transplant approach with mixed xenogeneic chimerism using
optimal GM pigs with intrabone injection (IBBMTx) of pig bone marrow. In Project 2, “Achieving Xenograft
Tolerance through Mixed Chimerism”, Aim 1 will build on our demonstration of greatly prolonged mixed chimerism
in baboons receiving IBBMTx of hCD47 Tg/hCRP Tg/GalT KO pig HCs and evaluate the utility of adding human
cytokine receptor genes to the pig. Aim 2 will build on our observation that expanded recipient baboon Tregs can
prolong mixed porcine chimerism and skin graft survival. We will combine the optimal pig from Aim 1 with optimized
ex-vivo expanded recipient Tregs and IBBMTx to achieve durable chimerism and, with it, tolerance of B cells and
NK cells in addition to T cells. Aim 3 will test whether or not the optimized mixed chimerism approach leads to
tolerance of renal xenografts, including baboons with high pre-formed non-Gal Nab levels, which will receive delayed
donor kidney transplantation. Project 3, “Tolerance of Adaptive and Innate Human Anti-Pig Immune Responses
in Humanized Mice”, builds on our studies of mixed xenogeneic chimerism and porcine thymic transplantation in
human immune system (HIS) mice. In Aim 1, we attempt to achieve optimal tolerance and immune function by
combining mixed chimerism with either hybrid thymic transplantation or pig plus human thymic transplantation,
modeling pig thymic transplantation without human host thymectomy. In Aim 2, we will determine the
mechanisms of T and B cell tolerance via mixed chimerism and thymic transplantation. Both aims utilize unique
TCR transgenic tools. Core A will provide administrative support, coordinating interactions among investigators
and NIH Program staff. Core B will support large animal needs, supplying baboons; coordinating the production,
quality control, phenotyping and genotyping of GM miniature swine; providing swine and baboon CMV assays;
and providing mAbs for all Projects. In Core C, CRISPR/Cas9 will be used to enable the construction of advanced
GM pigs. A Biobank and associated unified database wil...

## Key facts

- **NIH application ID:** 10327997
- **Project number:** 2P01AI045897-21A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DAVID H SACHS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,294,103
- **Award type:** 2
- **Project period:** 2000-09-15 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327997

## Citation

> US National Institutes of Health, RePORTER application 10327997, A Tolerance Approach to Xenotransplantation (2P01AI045897-21A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10327997. Licensed CC0.

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